WO2022013467A1 - Ruthenium complexes - Google Patents
Ruthenium complexes Download PDFInfo
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- WO2022013467A1 WO2022013467A1 PCT/ES2021/070509 ES2021070509W WO2022013467A1 WO 2022013467 A1 WO2022013467 A1 WO 2022013467A1 ES 2021070509 W ES2021070509 W ES 2021070509W WO 2022013467 A1 WO2022013467 A1 WO 2022013467A1
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- WIPO (PCT)
- Prior art keywords
- complexes
- cymene
- ruthenium
- ruthenium complex
- water
- Prior art date
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- 150000003303 ruthenium Chemical class 0.000 title claims abstract description 14
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims abstract description 74
- 238000000034 method Methods 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 230000008569 process Effects 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 150000003003 phosphines Chemical class 0.000 claims description 26
- 150000004820 halides Chemical class 0.000 claims description 19
- 239000003446 ligand Substances 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000012327 Ruthenium complex Substances 0.000 claims description 15
- 229910052707 ruthenium Inorganic materials 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 14
- 229910052751 metal Inorganic materials 0.000 claims description 14
- 239000002184 metal Substances 0.000 claims description 14
- 230000005595 deprotonation Effects 0.000 claims description 13
- 238000010537 deprotonation reaction Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- LAXRNWSASWOFOT-UHFFFAOYSA-J (cymene)ruthenium dichloride dimer Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Ru+2].[Ru+2].CC(C)C1=CC=C(C)C=C1.CC(C)C1=CC=C(C)C=C1 LAXRNWSASWOFOT-UHFFFAOYSA-J 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- -1 transition metal salts Chemical class 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 230000005588 protonation Effects 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 2
- KCTAHLRCZMOTKM-UHFFFAOYSA-N tripropylphosphane Chemical compound CCCP(CCC)CCC KCTAHLRCZMOTKM-UHFFFAOYSA-N 0.000 claims description 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 2
- 229910002651 NO3 Inorganic materials 0.000 claims 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims 2
- 229910052723 transition metal Inorganic materials 0.000 claims 2
- SRGDVGLATSDYAV-UHFFFAOYSA-N P.C12CC3CC(CC(C1)C3)C2 Chemical compound P.C12CC3CC(CC(C1)C3)C2 SRGDVGLATSDYAV-UHFFFAOYSA-N 0.000 claims 1
- 150000004673 fluoride salts Chemical class 0.000 claims 1
- 150000004694 iodide salts Chemical class 0.000 claims 1
- IFXORIIYQORRMJ-UHFFFAOYSA-N tribenzylphosphane Chemical compound C=1C=CC=CC=1CP(CC=1C=CC=CC=1)CC1=CC=CC=C1 IFXORIIYQORRMJ-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 229940126601 medicinal product Drugs 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 14
- 230000004071 biological effect Effects 0.000 description 8
- 230000001093 anti-cancer Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- FXXRPTKTLVHPAR-UHFFFAOYSA-N 1,3,5-triaza-7-phosphaadamantane Chemical compound C1N(C2)CN3CN1CP2C3 FXXRPTKTLVHPAR-UHFFFAOYSA-N 0.000 description 2
- DRGAZIDRYFYHIJ-UHFFFAOYSA-N 2,2':6',2''-terpyridine Chemical compound N1=CC=CC=C1C1=CC=CC(C=2N=CC=CC=2)=N1 DRGAZIDRYFYHIJ-UHFFFAOYSA-N 0.000 description 2
- 229940125650 NAMI-A Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003304 ruthenium compounds Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- MYAJTCUQMQREFZ-UHFFFAOYSA-K tppts Chemical compound [Na+].[Na+].[Na+].[O-]S(=O)(=O)C1=CC=CC(P(C=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=C(C=CC=2)S([O-])(=O)=O)=C1 MYAJTCUQMQREFZ-UHFFFAOYSA-K 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- FXPOFKKXWXRASA-UHFFFAOYSA-N 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane Chemical compound C1N(C)CP2CN(C)CN1C2 FXPOFKKXWXRASA-UHFFFAOYSA-N 0.000 description 1
- 241001120493 Arene Species 0.000 description 1
- YYCPSEFQLGXPCO-SECBINFHSA-N CC(C)C1=CC[C@@H](C)CC1 Chemical compound CC(C)C1=CC[C@@H](C)CC1 YYCPSEFQLGXPCO-SECBINFHSA-N 0.000 description 1
- CUUOXQDQFQPVLB-ASKATJPDSA-N CCC(C1)[C@@H](C)C=C[C@H]1C(C)C Chemical compound CCC(C1)[C@@H](C)C=C[C@H]1C(C)C CUUOXQDQFQPVLB-ASKATJPDSA-N 0.000 description 1
- 0 CNCP(CNC)(CN(C)*)*(Cl)Cl Chemical compound CNCP(CNC)(CN(C)*)*(Cl)Cl 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 229910019131 CoBr2 Inorganic materials 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108020005124 DNA Adducts Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229940125661 RAPTA-C Drugs 0.000 description 1
- 229910019891 RuCl3 Inorganic materials 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- AFTJNIKGLUJJPI-UHFFFAOYSA-N acetic acid;cyclohexane-1,2-diamine Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.NC1CCCCC1N AFTJNIKGLUJJPI-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical class [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002468 redox effect Effects 0.000 description 1
- 229940125657 ruthenium arene PTA Drugs 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- NTUROZDXWLPVHB-UHFFFAOYSA-M sodium;3-diphenylphosphanylbenzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NTUROZDXWLPVHB-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical class CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
Definitions
- the present invention falls within the technical field of compounds with biological properties and, in particular, with anticancer activity. More specifically, the invention is related to ruthenium complexes, as well as their production process and their uses.
- Cancer is one of the diseases that currently has the greatest impact on modern society, being the first reason for death in the Western world.
- the number of useful drugs for the treatment of cancer is very limited, despite the efforts made in their research to date.
- One of the known drugs with anticancer activity is cis-diamindichloroplatinum(ll), whose properties were discovered by B. Rosenberg in the 1960s (see Rosenberg, B.; Van Camp, L; Krigas, T .; Nature 1965, 205, 698). Both this compound and its carboplatin derivative are among the most widely used anticancer drugs in the clinical setting.
- Pt complexes have serious drawbacks for the patient, due to their high toxicity, and they also have a high cost of obtaining them.
- An alternative to Pt complexes are metallic compounds based on other metals, among which ruthenium (Ru) complexes stand out.
- NAMI-A does not inhibit primary tumor growth, but rather its main activity involves slowing the rate at which metastasis occurs, (see G. Sava, S. Zorzet, C. Turrin, F. Vita, M. Soranzo, G. Zabucchi, M. Cocchietto, A. Bergamo, S. DiGiovine, G. Pezzoni, L. Sartor, S. Garbisa, Clin. Cancer Res. 2003, 9, 1898-1905).
- the different hydrophilic and lipophilic balances are essential for the in vivo behavior and efficacy of metal complexes under physiological conditions.
- these must be sufficiently soluble in water (since it is the main component of physiological fluids), but also in organic media, to pass through the cell membrane.
- phosphines ligands, arenes and aryls contribute not only to optimize such equilibria in metal complexes which are mainly in the 2 and 3 transition series, but also to regulate redox properties and steric factors (see C. Gaiddon, M.Pfeffer. Eur. J. Inorg. Chem. 2017, 1639-1654).
- Ru(ll) a family of compounds of the RuCl ⁇ 6-arene)(1icP-PTA) type, known generically as RAPTA, has been described.
- RAPTA-C binds to the DNA molecule, fixing it and increasing the fusion point of the DNA adduct -RAPTA- c.
- they are capable of interacting with histones, as well as with the RNA of the intracellular medium (see F. Scalambra, P. Lorenzo, I. de los R ⁇ os, A. Romerosa. Eur.
- Ru(ll) compounds bound to ligands such as PPhb, PTA, and mPTA (see Antonio M. Romerosa, Tatiana Campos Malpartida, Chaker Lidr ⁇ ssi, Mustapha Saoud, Manuel Serrano Ru ⁇ z, Mauricio Peruzzini, Carlos Antonio Garrido Cárdenas, Federico Garc ⁇ a Maroto Inorg Chem 2006, 45, 1289-1298 ;and Antonio Romerosa, Mustapha Saoud, Tatiana Campos-Malpartida, Chaker Lidr ⁇ ssi, Manuel Serrano-Ruiz, Maurizio Peruzzini, Jose Antonio Garrido-Cárdenas, Federico Garc ⁇ a-Maroto, Eur. J. Inorg Chem. 2007, 2803-2812) have shown that they have good activity against DNA, and are also very soluble in water, which constitutes an additional advantage for their use as starting compounds
- the present invention is aimed at solving said needs by means of novel ruthenium complexes, as well as their procedures for obtaining and corresponding uses.
- a first object of the invention relates to a novel class of Ru complexes that have great stability, hydrophilic/hydrophobic balance, ease of preparation, hydrosolubility and liposolubility. Said object is achieved by combining said complexes with ligands derived from 1,3,5-triaza-7-phosphaadamantane, known as PTA: PTA is, in general, a ligand that provides stability and a good hydrophilic/hydrophobic balance suitable for the complex it constitutes.
- dmoPTA 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane
- HdmoPTA 3,7-H-3,7-dimethyl -1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane
- a second object of the present invention is a process for obtaining ruthenium complexes of general formula I and II.
- the procedures start either from the complex of ruthenium with p-cymene, or from a halogen of ruthenium.
- substitution occurs with the dmPTA ligand, which opens during the reaction, giving rise to the HdmoPTA compound, or it starts directly from the reaction with that ligand, but deprotonated.
- Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 .
- the compounds have a better way of preparation, conservation and administration, as well as a high biological activity accompanied by a high specificity against different tumors.
- the specific composition of the complex determines its activity and selectivity, which, in addition, presents a low toxicity against the rest of the cells of the organism, typical of Ru complexes.
- the dmoPTA ligand is coordinated by the P atom to Ru, it can be coordinated again to another metal in a salt through the N atoms bearing the CH 3 groups.
- This coordination allows bis-heterometallic products to be obtained, if the starting complex only has one dmoPTA (see diagram below, it reacts with a bivalent metal halide-MY 2 ), tris-heterometallic, if it has two dmoPTA, and tetra - heterometallic, if it has three dmoPTA.
- the compounds obtained can react through the metals attached to the CH 3 N atoms to give rise to polyheterometallic systems.
- Type I complexes would be obtained from type II complexes by deprotonation with a strong or medium-strength base, such as NaOH, KOH, NH 3 .
- Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 .
- Type I complexes would be obtained from type II, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 .
- Figure 4 shows a direct reaction of [Ru(p-cymene)Cl 2 ] 2 with an alkaline halide, with dmoPTA (to obtain type I) and subsequent reaction with phosphines soluble in water or in organic solvents, according to a preferred embodiment. of the invention.
- Type II complexes are obtained by protonation of type I complexes with a strong or mild acid, such as HCI, HCF 3 SO 3 , H 2 S0 4 , H 3 P0 4 , HCI0 4 or CH 3 CH 2 COOH.
- the first aspect of the invention relates to water-soluble ruthenium complexes, comprising derivatives of dmoPTA (type I) and HdmoPTA (type II), with p-cymene, hydro and/or liposoluble halides and phosphines:
- Ru represents a ruthenium atom
- the ruthenium metal atom exhibits high biological activity. Furthermore, it has been observed that its activity against biomolecules is intensified when it is coordinated to the phosphine dmoPTA (type I complexes) and HdmoPTA (type II complexes).
- a preferred embodiment of the invention is considered to be any ruthenium complex of formula I and II in which Q and X represent the same or different ligand: F, Cl, Br, I; the fat-soluble phosphines triphenylphosphine, trimethylphosphines, triethylphosphine, tripropylphosphine, tributylphosphine; the water-soluble phosphines PTA (adamantanephosphine), dmPTA (dimethyladamantanephosphine), mPTA (methyladamantanephosphine) and phosphines with sulfonate, phosphate, carbonate, amine, ammonium, carboxylate, alcohol, aldehyde groups and mixtures thereof.
- mixtures refer to phosphines that possess two or more of the aforementioned functional groups.
- the second aspect of the invention refers to the different processes for obtaining ruthenium complexes of general formula I and II.
- the components and substituents have the same meaning as given above when describing the ruthenium complexes of general formula I and II.
- the procedures start either from the complex of ruthenium with p-cymene, or from a halogen of ruthenium.
- substitution occurs with the dmPTA ligand, which opens during the reaction, giving rise to the HdmoPTA compound, or it starts directly from the reaction with that ligand, but deprotonated.
- Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 ( Figure 2 herein).
- Type II complexes are obtained by protonation of type I complexes with a strong or mild acid, such as HCl, HCF 3 SO 3 , H 2 SO 4 , H 3 PO 4 , HCIO 4 or CH 3 CH 2 COOH ( Figure 4 of this document).
- a strong or mild acid such as HCl, HCF 3 SO 3 , H 2 SO 4 , H 3 PO 4 , HCIO 4 or CH 3 CH 2 COOH
- Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base such as NaOH, KOH, NH3 or other similar inorganic and organic bases.
- a strong or medium base such as NaOH, KOH, NH3 or other similar inorganic and organic bases.
- the type I compound is obtained by deprotonation of the type I compound.
- the complexes obtained in the previous stage, once purified, are reacted
- reaction medium that preferably comprises a solvent or mixture of solvents selected from water, ethanol, methanol, ethyl acetate, isopropanol, tertbutanol, ethylene glycol, diglyme (Bis(2-methoxyethyl) ether ), glyme (Glycol dimethyl ether), chloroform, dichloromethane, benzene, toluene, acetone, tetrahydrofuran, dioxane, acetonitrile. Ethanol, acetone and water, and mixtures thereof, are especially preferred.
- solvent or mixture of solvents selected from water, ethanol, methanol, ethyl acetate, isopropanol, tertbutanol, ethylene glycol, diglyme (Bis(2-methoxyethyl) ether ), glyme (Glycol dimethyl ether), chloroform, dichloromethane, benzene, toluen
- the above procedures can be carried out under temperature conditions between -60° C to 150° C and between 0.5 and 100 atmospheres of pressure, with or without stirring.
- the reactions are carried out at a temperature range of 5°C to 60°C and with pressures between 0.5 and 10 atmospheres.
- the ruthenium salts (RL1Y3) used in the context of the present invention may preferably be selected from soluble ruthenium halides.
- composition with biological activity that comprises a ruthenium complex of general formula I and/or II, combined with any additional compound with biological activity.
- dmPTA bismethyl-1,3,5-triaza-7 -phosphaadamantane
- Multimetallic compounds would be obtained from complexes with one, two or three HdmoPTA or dmoPTA, by reaction with metal salts.
- the complex showed an antiproliferative activity indicated by the cell survival half-life factor (IC50) of 32.09 ⁇ 0.30 mM against that of cisplatin which, in the same experiment, was 45.6 ⁇ 8.08 mM.
- IC50 cell survival half-life factor
- Three examples of bi-heterometallic compounds that would be obtained from this compound show better activity as shown by their IC50: IC50 Ru-Zn: 9.07 ⁇ 0.27;
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Abstract
The present invention relates to a new variety of ruthenium complexes comprising a Ru derivative with p-cymene and dmoPTA or HdmoPTA. These complexes combine water solubility, high level of activity and specificity against different biomolecules, as well as air stability and easy administration. Additionally, the complexes exhibit biomolecule-specific activity, both in strength and activity, forming the basis for a range of drugs that can act specifically on certain targets and against the diseases in which they are implicated. The invention also relates to different processes for obtaining the aforementioned ruthenium complexes and to their use as medicinal products or in the treatment of cancer.
Description
DESCRIPCIÓN DESCRIPTION
COMPLEJOS DE RUTENIO RUTHENIUM COMPLEXES
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención se enmarca en el campo técnico de los compuestos con propiedades biológicas y, en particular, con actividad anticancerígena. Más concretamente, la invención se relaciona con complejos de rutenio, así como con su procedimiento de obtención y sus usos. The present invention falls within the technical field of compounds with biological properties and, in particular, with anticancer activity. More specifically, the invention is related to ruthenium complexes, as well as their production process and their uses.
ANTECEDENTES DE LA INVENCIÓN BACKGROUND OF THE INVENTION
El cáncer es una de las enfermedades que mayor impacto tiene actualmente en la sociedad moderna, siendo la primera razón de muerte en el mundo occidental. El número de fármacos útiles para el tratamiento del cáncer es muy limitado, a pesar de los esfuerzos realizados su investigación hasta la fecha. Uno de los fármacos conocidos que presenta actividad contra el cáncer es el cis-diamindicloroplatino(ll), cuyas propiedades fueron descubiertas por B. Rosenberg en los años 60 del siglo XX (ver Rosenberg, B.; Van Camp, L; Krigas, T.; Nature 1965, 205, 698). Tanto este compuesto como su derivado carbo- platino son de los fármacos anticancerígenos más utilizados en el ámbito clínico. No obstante, y a pesar de su utilidad, los complejos de platino (Pt) presentan graves inconvenientes para el paciente, por su alta toxicidad, y también poseen un coste elevado de obtención. Una alternativa a los complejos de Pt son los compuestos metálicos basados en otros metales, de entre los que destacan los complejos de rutenio (Ru). Cancer is one of the diseases that currently has the greatest impact on modern society, being the first reason for death in the Western world. The number of useful drugs for the treatment of cancer is very limited, despite the efforts made in their research to date. One of the known drugs with anticancer activity is cis-diamindichloroplatinum(ll), whose properties were discovered by B. Rosenberg in the 1960s (see Rosenberg, B.; Van Camp, L; Krigas, T .; Nature 1965, 205, 698). Both this compound and its carboplatin derivative are among the most widely used anticancer drugs in the clinical setting. However, despite their usefulness, platinum (Pt) complexes have serious drawbacks for the patient, due to their high toxicity, and they also have a high cost of obtaining them. An alternative to Pt complexes are metallic compounds based on other metals, among which ruthenium (Ru) complexes stand out.
Uno de los primeros compuestos de rutenio con estado de oxidación +2 (Ru(ll)) estudiados es el cis-[Ru(bpy)2(NH3)2]2+ (bpy = 2,2' bipiridina), análogo al cisplatino pero sin su elevada actividad anticancerígena. Otros ejemplos son el fac-[RuCl3(NH3)2] (ver Clarke, M.J.; Zhu, F.; Frasca, D.R. Chem. Rev. 1999, 99, 2511-2534 ; y Clarke, M.J. Met. lons Biol. Syst. 1980, 11, 231-283), el trans-[Hln][RuCL(lnd)2] (Ind = Indazol), merc-[Ru(terpy)Cl3] (terpy = 2,2’- terpiridina), [Ru(chd-H2)Cl2] (chd = 1 ,2-ciclohexanodiamin-tetraacetato), (ver Keppler, B.K.; Flenn, M.; Juhl, U.M.; Berger, M.R.; Niebl, R.; Wagner, F.E. Prog. Clin. Biochem. Med. 1989, 10, 41-69 ; Navakova,0.; Kasparova, J.; Vrana, O.; Van Vliet, P.M.; Reedijk, J.; Brabec, V. Biochemistry 1995, 34, 12369-2378 ; Vilaplana, R.A.; González-Vílchez, F.; Gutiérrez- Puebla, E.; Ruíz-Valero, C. Inorg. Chim. Acta 1994, 224, 15-18 ; y Sava, G.; Gagliardi, R.; Bergamo, A.; Alessio, £.; Mestroni, G. Anticancer Res. 1999, 19, 969-972). De entre los
complejos de distintos metales estudiados, los de Ru(ll) se han probado más activos que los de Ru(lll), si bien otros factores como la solubilidad en agua de los complejos, o su coeficiente de reparto (razón entre la solubilidad en ambientes lipofílicos y fóbicos), afectan también a la actividad antiproliferativa de los mismos. One of the first ruthenium compounds with oxidation state +2 (Ru(ll)) studied is cis-[Ru(bpy)2(NH3)2] 2+ (bpy = 2,2' bipyridine), analogous to cisplatin but without its high anticancer activity. Other examples are fac-[RuCl3(NH3)2] (see Clarke, MJ; Zhu, F.; Frasca, DR Chem. Rev. 1999, 99, 2511-2534; and Clarke, MJ Met. lons Biol. Syst. 1980, 11, 231-283), trans-[Hln][RuCL(lnd)2] (Ind = Indazole), merc-[Ru(terpy)Cl3] (terpy = 2,2'- terpyridine), [Ru (chd-H2)Cl2] (chd = 1,2-cyclohexanediamin-tetraacetate), (see Keppler, BK; Flenn, M.; Juhl, UM; Berger, MR; Niebl, R.; Wagner, FE Prog. Clin. Biochem Med 1989, 10, 41-69, Navakova, O., Kasparova, J, Vrana, O, Van Vliet, PM, Reedijk, J, Brabec, V. Biochemistry 1995, 34, 12369-2378; Vilaplana, RA, González-Vílchez, F., Gutiérrez-Puebla, E., Ruíz-Valero, C. Inorg.Chim.Acta 1994, 224, 15-18 , and Sava, G., Gagliardi, R., Bergamo, A., Alessio, £., Mestroni, G. Anticancer Res. 1999, 19, 969-972). Among the complexes of different metals studied, those of Ru(ll) have proven more active than those of Ru(lll), although other factors such as the solubility in water of the complexes, or their partition coefficient (ratio between the solubility in environments lipophilic and phobic), also affect their antiproliferative activity.
La administración y el transporte de estos complejos a través de organismos vivos requiere que su solubilidad en agua sea la mayor posible. En este sentido, los complejos metálicos con mayor solubilidad en agua son aquellos con ligandos hidrosolubles. El mejor ejemplo de este tipo de compuestos lo constituye el trans-[RuCÍ4(DMSO)lm][lmH] (NAMI-A), que ha sido el compuesto de rutenio conocido que ha conseguido superar mayor número de ensayos clínicos (ver G. Sava, R.Gagliardi, A. Bergamo, E. Alessio, G. Mestroni, Anticancer Res. 1999, 19, 962-972 ; y M. Galanski, V. B. Arion, M. A. Jakupec, B. K. Keppler, Curr. Pharm. Des. 2003, 9, 2078-2089). A diferencia del cisplatino, el NAMI-A no inhibe el crecimiento del tumor primario, sino que su actividad principal implica la disminución de la velocidad a la que se produce la metástasis, (ver G. Sava, S. Zorzet, C. Turrin, F. Vita, M. Soranzo, G. Zabucchi, M. Cocchietto, A. Bergamo, S. DiGiovine, G. Pezzoni, L.Sartor, S. Garbisa, Clin. Cáncer Res. 2003, 9, 1898 -1905). Administration and transport of these complexes through living organisms requires their solubility in water to be as high as possible. In this sense, the metal complexes with greater water solubility are those with water-soluble ligands. The best example of this type of compound is trans-[RuCÍ4(DMSO)lm][lmH] (NAMI-A), which has been the known ruthenium compound that has managed to pass the largest number of clinical trials (see G. Sava, R.Gagliardi, A. Bergamo, E. Alessio, G. Mestroni, Anticancer Res. , 9, 2078-2089). Unlike cisplatin, NAMI-A does not inhibit primary tumor growth, but rather its main activity involves slowing the rate at which metastasis occurs, (see G. Sava, S. Zorzet, C. Turrin, F. Vita, M. Soranzo, G. Zabucchi, M. Cocchietto, A. Bergamo, S. DiGiovine, G. Pezzoni, L. Sartor, S. Garbisa, Clin. Cancer Res. 2003, 9, 1898-1905).
Asimismo, los diferentes equilibrios hidrofílico y lipofílico son esenciales para el comportamiento in vivo y la eficacia de los complejos metálicos bajo condiciones fisiológicas. Así pues, éstos deben ser suficientemente solubles en agua (ya que es el principal componente de los fluidos fisiológicos), pero también en medios orgánicos, para pasar a través de la membrana celular. En este contexto, se ha observado que la combinación de ligandos fosfanos, árenos y arilos contribuyen, no sólo a optimizar este tipo de equilibrios en los complejos de metales que están principalmente en la 2a y 3a series de transición, sino también a regular las propiedades redox y los factores estéricos (ver C. Gaiddon, M.Pfeffer. Eur. J. Inorg. Chem. 2017, 1639-1654). Also, the different hydrophilic and lipophilic balances are essential for the in vivo behavior and efficacy of metal complexes under physiological conditions. Thus, these must be sufficiently soluble in water (since it is the main component of physiological fluids), but also in organic media, to pass through the cell membrane. In this context, it has been observed that the combination of phosphines ligands, arenes and aryls contribute not only to optimize such equilibria in metal complexes which are mainly in the 2 and 3 transition series, but also to regulate redox properties and steric factors (see C. Gaiddon, M.Pfeffer. Eur. J. Inorg. Chem. 2017, 1639-1654).
En el caso del Ru(ll), se ha descrito una familia de compuestos de tipo RuCI^6- areno)(1icP-PTA), conocidos genéricamente como RAPTA. Además de su baja citotoxicidad en comparación con el cisplatino, los estudios realizados con ADN comercial (de timo de ternera), sugieren que el RAPTA-C se enlaza a la molécula de ADN fijándola y aumentando el punto de fusión del aducto ADN - RAPTA-C. No obstante, a pesar de no mostrar un enlace selectivo frente a ADN in vitro, sí son capaces de interaccionar con las histonas, así como con el ARN del medio intracelular (ver F. Scalambra, P. Lorenzo, I. de los Ríos, A. Romerosa. Eur. J. Inorg. Chem., 2019, 1529-1538).
Los compuestos de Ru(ll) unidos a ligandos tales como PPhb, PTA y mPTA (ver Antonio M. Romerosa, Tatiana Campos Malpartida, Chaker Lidríssi, Mustapha Saoud, Manuel Serrano Ruíz, Mauricio Peruzzini, José Antonio Garrido Cárdenas, Federico García Maroto Inorg. Chem. 2006, 45, 1289-1298 ; y Antonio Romerosa, Mustapha Saoud, Tatiana Campos-Malpartida, Chaker Lidríssi, Manuel Serrano-Ruiz, Maurizio Peruzzini, José Antonio Garrido-Cárdenas, Federico García-Maroto, Eur. J. Inorg. Chem. 2007, 2803-2812) han demostrado que presentan una buena actividad frente a ADN, siendo además muy solubles en agua, lo que constituye una ventaja adicional para su uso como compuestos de partida para la síntesis de nuevos fármacos. In the case of Ru(ll), a family of compounds of the RuCl^6-arene)(1icP-PTA) type, known generically as RAPTA, has been described. In addition to its low cytotoxicity compared to cisplatin, studies carried out with commercial DNA (from calf thymus), suggest that RAPTA-C binds to the DNA molecule, fixing it and increasing the fusion point of the DNA adduct -RAPTA- c. However, despite not showing a selective binding against DNA in vitro, they are capable of interacting with histones, as well as with the RNA of the intracellular medium (see F. Scalambra, P. Lorenzo, I. de los Ríos, A. Romerosa. Eur. J. Inorg. Chem., 2019, 1529-1538). Ru(ll) compounds bound to ligands such as PPhb, PTA, and mPTA (see Antonio M. Romerosa, Tatiana Campos Malpartida, Chaker Lidríssi, Mustapha Saoud, Manuel Serrano Ruíz, Mauricio Peruzzini, José Antonio Garrido Cárdenas, Federico García Maroto Inorg Chem 2006, 45, 1289-1298 ;and Antonio Romerosa, Mustapha Saoud, Tatiana Campos-Malpartida, Chaker Lidríssi, Manuel Serrano-Ruiz, Maurizio Peruzzini, José Antonio Garrido-Cárdenas, Federico García-Maroto, Eur. J. Inorg Chem. 2007, 2803-2812) have shown that they have good activity against DNA, and are also very soluble in water, which constitutes an additional advantage for their use as starting compounds for the synthesis of new drugs.
Si bien, como se ha descrito, el avance en la mejora de los complejos de rutenio frente al cáncer ha sido considerable en los últimos años, existen aún algunas limitaciones en los mismos que sería deseable superar. Por ejemplo, existe aún la necesidad, en el presente campo técnico, de obtener complejos mejorados que consigan estabilizar el estado de oxidación del átomo de Ru, proporcionando al mismo tiempo un balance hidrofílico/hidrofóbico adecuado en dichos complejos. También existe, en el citado campo, una necesidad de obtener complejos de Ru estables, fáciles de preparar y que posean una alta solubilidad en agua y en disolventes orgánicos, así como una alta liposolubilidad. Although, as has been described, progress in improving ruthenium complexes against cancer has been considerable in recent years, there are still some limitations that it would be desirable to overcome. For example, there is still a need, in the present technical field, to obtain improved complexes that manage to stabilize the oxidation state of the Ru atom, while providing an adequate hydrophilic/hydrophobic balance in said complexes. There is also, in the aforementioned field, a need to obtain stable Ru complexes that are easy to prepare and that have a high solubility in water and in organic solvents, as well as a high lipid solubility.
La presente invención está orientada a resolver dichas necesidades mediante unos novedosos complejos de rutenio, así como de sus procedimientos de obtención y usos correspondientes. The present invention is aimed at solving said needs by means of novel ruthenium complexes, as well as their procedures for obtaining and corresponding uses.
DESCRIPCIÓN BREVE DE LA INVENCIÓN BRIEF DESCRIPTION OF THE INVENTION
Según lo descrito en el apartado precedente, un primer objeto de la invención se refiere a una novedosa clase de complejos de Ru que presenta gran estabilidad, balance hidrofílico/hidrofóbico, facilidad de preparación, hidrosolubilidad y liposolubilidad. Dicho objeto se realiza mediante la combinación de dichos complejos con ligandos derivados del 1 ,3,5-triaza-7-fosfaadamantano, conocido como PTA:
El PTA es, por lo general, un ligando que proporciona estabilidad y un buen balance hidrofílico/hidrofóbico adecuado al complejo que constituye. Asimismo, se ha encontrado que los derivados del PTA 3,7-dimetil-1 ,3,7-triaza-5-fosfabiciclo[3.3.1]nonano (denominado como dmoPTA) y 3,7-H-3,7-dimetil-1 ,3,7-triaza-5-fosfabiciclo[3.3.1]nonano (HdmoPTA) son excelentes ligandos, que estabilizan el estado de oxidación +2 en el átomo de Ru y que, además, son fáciles de preparar y solubles en agua y disolventes orgánicos. Ambos pueden, además, someterse con facilidad a procesos de protonización o desprotonización, respectivamente, en función del nivel de liposolubilidad que se desee obtener. Ambos ligandos se muestran a continuación:
As described in the preceding section, a first object of the invention relates to a novel class of Ru complexes that have great stability, hydrophilic/hydrophobic balance, ease of preparation, hydrosolubility and liposolubility. Said object is achieved by combining said complexes with ligands derived from 1,3,5-triaza-7-phosphaadamantane, known as PTA: PTA is, in general, a ligand that provides stability and a good hydrophilic/hydrophobic balance suitable for the complex it constitutes. Likewise, it has been found that the PTA derivatives 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (referred to as dmoPTA) and 3,7-H-3,7-dimethyl -1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (HdmoPTA) are excellent ligands, which stabilize the +2 oxidation state on the Ru atom and are also easy to prepare and soluble in water and organic solvents. Both can also be easily subjected to protonation or deprotonation processes, respectively, depending on the desired level of lipid solubility. Both ligands are shown below:
Más concretamente, la presente invención propone el uso de compuestos de Ru con p- cimeno y HdmoPTA o dmoPTA, fosfinas liposolubles y/o hidrosolubles y haluros, de fórmula general I y II (ver a continuación) y que presentan actividad biológica, en particular frente a células cancerosas:
donde Ru representa un átomo de rutenio y Q, X representan halógenos o fosfinas liposolubles y/o hidrosolubles, la carga n = 0, 1, 2, 3; incluyendo el HdmoPTA y el dmoPTA. More specifically, the present invention proposes the use of Ru compounds with p-cymene and HdmoPTA or dmoPTA, fat-soluble and/or water-soluble phosphines and halides, of general formula I and II (see below) and which have biological activity, in particular against cancer cells: where Ru represents a ruthenium atom and Q, X represent halogens or fat-soluble and/or water-soluble phosphines, the charge n = 0, 1, 2, 3; including the HdmoPTA and the dmoPTA.
Dichos complejos conjugan tanto solubilidad en agua, elevada actividad y especificidad frente a diferentes biomoléculas, como estabilidad al aire y fácil administración. Ventajosamente, la actividad biológica de estos compuestos es mayor o, al menos, diferente a la actividad biológica de sus partes. Asimismo, debido a la enorme variedad de compuestos que se pueden obtener mediante las fórmulas generales I y II, algunos de ellos
pueden presentar actividad específica frente a las biomoléculas, tanto en intensidad como en actividad. Estos compuestos constituyen, pues, la base de una serie de fármacos que pueden actuar a la carta, específicamente frente a ciertas biomoléculas diana y a las enfermedades en las que participan. These complexes combine both solubility in water, high activity and specificity against different biomolecules, as well as stability in air and easy administration. Advantageously, the biological activity of these compounds is greater than, or at least different from, the biological activity of their parts. Likewise, due to the enormous variety of compounds that can be obtained by means of general formulas I and II, some of them they can present specific activity against biomolecules, both in intensity and in activity. These compounds thus constitute the basis for a series of drugs that can act on demand, specifically against certain target biomolecules and the diseases in which they are involved.
Un segundo objeto de la presente invención es un procedimiento para la obtención de los complejos de rutenio de fórmula general I y II. Los procedimientos parten bien del complejo de rutenio con p-cimeno, o bien de un halógeno de rutenio. En el primer caso, se produce la sustitución con el ligando dmPTA, que durante la reacción se abre dando lugar al compuesto HdmoPTA, o bien se parte directamente de la reacción con ese ligando, pero desprotonado. La combinación de las diferentes posibilidades de obtención dan lugar a cuatro procedimientos diferentes para obtener dichos complejos: a) Reacción del complejo [Ru(p-cimeno)Y2]2 (Y = halógeno) con dmPTA (CF3SC>3)2 (dmPTA = dimetiladamantanofosfina), y posterior reacción con fosfinas solubles (Q) en agua o en disolventes orgánicos (Figura 1). Los complejos tipo I se obtendrían de los complejos tipo II por desprotonación con una base fuerte o de mediana fortaleza, tal como NaOH, KOH, NH3. b) Reacción directa de un haluro de rutenio (RUY3; Y = F, Cl, Br, I) con p-cimeno, con dmPTA y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos (Figura 2). Los complejos tipo I se obtendrían de los complejos tipo II, por desprotonación con una base fuerte o mediana, tal como NaOH, KOH, NH3. c) Reacción directa de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino (AlcY; Y = F, Cl, Br, I), con HdmoPTA(CF3S03) (para II) y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos (Figura 3). Los complejos tipo I se obtendrían del tipo II, por desprotonación con una base fuerte o mediana, tal como NaOH, KOH, NH3. d) Reacción directa de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino, con dmoPTA (para obtener el tipo I) y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos (Figura 4). Los complejos tipo II se obtienen por protonación de los complejos de tipo I con un ácido fuerte o mediano, tal como HCI, HCF3SO3, H2SO4, H3PO4, HCIO4 o CH3CH2COOH.
Los compuestos anteriores, que se definen mediante las fórmulas generales I y II descritas, aúnan propiedades anticancerígenas incrementadas respecto a las partes que los componen, presentando mayor coeficiente de reparto (solubilidad en agua y en lípidos) que las partes de las que están compuestos y resistencia a su descomposición bajo aire. Los compuestos poseen una mejor forma de preparación, conservación y administración, así como una elevada actividad biológica acompañada de una alta especificidad frente a diferentes tumores. Asimismo, y según lo mencionado, la composición concreta del complejo determina su actividad y selectividad que, además, presenta una baja toxicidad frente al resto de células del organismo, típica de los complejos de Ru. A second object of the present invention is a process for obtaining ruthenium complexes of general formula I and II. The procedures start either from the complex of ruthenium with p-cymene, or from a halogen of ruthenium. In the first case, substitution occurs with the dmPTA ligand, which opens during the reaction, giving rise to the HdmoPTA compound, or it starts directly from the reaction with that ligand, but deprotonated. The combination of the different possibilities of obtaining give rise to four different procedures to obtain said complexes: a) Reaction of the complex [Ru(p-cymene)Y2]2 (Y = halogen) with dmPTA (CF3SC>3)2 (dmPTA = dimethyl adamantane phosphine), and subsequent reaction with soluble phosphines (Q) in water or organic solvents (Figure 1). Type I complexes would be obtained from type II complexes by deprotonation with a strong or medium-strength base, such as NaOH, KOH, NH 3 . b) Direct reaction of a ruthenium halide (RUY3; Y = F, Cl, Br, I) with p-cymene, with dmPTA and subsequent reaction with phosphines soluble in water or in organic solvents (Figure 2). Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 . c) Direct reaction of [Ru(p-cymene)Cl2]2 with an alkaline halide (AlcY; Y = F, Cl, Br, I), with HdmoPTA(CF 3 S0 3 ) (for II) and subsequent reaction with phosphines soluble in water or in organic solvents (Figure 3). Type I complexes would be obtained from type II, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 . d) Direct reaction of [Ru(p-cymene)Cl 2 ] 2 with an alkaline halide, with dmoPTA (to obtain type I) and subsequent reaction with phosphines soluble in water or in organic solvents (Figure 4). Type II complexes are obtained by protonating type I complexes with a strong or mild acid, such as HCl, HCF3SO3, H2SO4, H3PO4, HCIO4, or CH3CH2COOH. The above compounds, which are defined by the general formulas I and II described, combine increased anticancer properties with respect to the parts that compose them, presenting a higher partition coefficient (solubility in water and in lipids) than the parts of which they are composed and resistance to decomposition in air. The compounds have a better way of preparation, conservation and administration, as well as a high biological activity accompanied by a high specificity against different tumors. Likewise, and as mentioned, the specific composition of the complex determines its activity and selectivity, which, in addition, presents a low toxicity against the rest of the cells of the organism, typical of Ru complexes.
Una vez coordinado el ligando dmoPTA por el átomo de P al Ru, puede coordinarse nuevamente a otro metal de una sal a través de los átomos de N que soportan los grupos CH3. Esta coordinación permite obtener productos bis-heterometálicos, si el complejo de partida sólo dispone de un dmoPTA (ver esquema a continuación, se reaciona con un haluro de metal bivalente-MY2), tris-heterometálicos, si dispone de dos dmoPTA, y tetra- heterometálicos, si dispone de tres dmoPTA.
Once the dmoPTA ligand is coordinated by the P atom to Ru, it can be coordinated again to another metal in a salt through the N atoms bearing the CH 3 groups. This coordination allows bis-heterometallic products to be obtained, if the starting complex only has one dmoPTA (see diagram below, it reacts with a bivalent metal halide-MY 2 ), tris-heterometallic, if it has two dmoPTA, and tetra - heterometallic, if it has three dmoPTA.
Además, los compuestos obtenidos pueden reaccionar a través de los metales unidos a los átomos CH3N para dar lugar a sistemas poliheterometálicos.
In addition, the compounds obtained can react through the metals attached to the CH 3 N atoms to give rise to polyheterometallic systems.
Otros objetos de la invención se refieren a los complejos monometálicos de rutenio, multimetálicos y polimetálicos según cualquiera de las realizaciones descritas en el
presente documento, para su uso como un medicamento, o para su uso en el tratamiento del cáncer. Other objects of the invention refer to ruthenium monometallic, multimetallic and polymetallic complexes according to any of the embodiments described in the herein, for use as a medicament, or for use in the treatment of cancer.
Los diferentes objetos de la invención se describen, en conjunto, en las reivindicaciones que se adjuntan en el presente documento. The different objects of the invention are described, as a whole, in the claims appended hereto.
DESCRIPCIÓN DE LOS DIBUJOS DESCRIPTION OF THE DRAWINGS
La Figura 1 muestra una reacción del complejo [Ru(p-cimeno)Y2]2 (Y = halógeno) con dmPTA (CF3S03)2 (dmPTA = dimetiladamantanofosfina), y posterior reacción con fosfinas solubles (Q) en agua o en disolventes orgánicos, según una realización preferente de la invención. Los complejos tipo I se obtendrían de los complejos tipo II por desprotonación con una base fuerte o de mediana fortaleza, tal como NaOH, KOH, NH3. Figure 1 shows a reaction of the complex [Ru(p-cymene)Y2]2 (Y = halogen) with dmPTA (CF 3 S0 3 ) 2 (dmPTA = dimethyladamantanophosphine), and subsequent reaction with soluble phosphines (Q) in water or in organic solvents, according to a preferred embodiment of the invention. Type I complexes would be obtained from type II complexes by deprotonation with a strong or medium-strength base, such as NaOH, KOH, NH 3 .
La Figura 2 muestra una reacción directa de un haluro de rutenio (RUY3; Y = F, Cl, Br, I) con p-cimeno, con dmPTA y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos, según una realización preferente de la invención. Los complejos tipo I se obtendrían de los complejos tipo II, por desprotonación con una base fuerte o mediana, tal como NaOH, KOH, NH3. Figure 2 shows a direct reaction of a ruthenium halide (RUY3; Y = F, Cl, Br, I) with p-cymene, with dmPTA and subsequent reaction with phosphines soluble in water or in organic solvents, according to a preferred embodiment of the invention. Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 .
La Figura 3 muestra una reacción directa de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino (AlcY; Y = F, Cl, Br, I), con HdmoPTA(CF3S03) (para II) y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos, según una realización preferente de la invención. Los complejos tipo I se obtendrían del tipo II, por desprotonación con una base fuerte o mediana, tal como NaOH, KOH, NH3. Figure 3 shows a direct reaction of [Ru(p-cymene)Cl2]2 with an alkali halide (AlcY; Y = F, Cl, Br, I), with HdmoPTA(CF 3 S0 3 ) (for II) and subsequent reaction with phosphines soluble in water or in organic solvents, according to a preferred embodiment of the invention. Type I complexes would be obtained from type II, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 .
La Figura 4 muestra una reacción directa de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino, con dmoPTA (para obtener el tipo I) y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos, según una realización preferente de la invención. Los complejos tipo II se obtienen por protonación de los complejos de tipo I con un ácido fuerte o mediano, tal como HCI, HCF3SO3, H2S04, H3P04, HCI04 o CH3CH2COOH. Figure 4 shows a direct reaction of [Ru(p-cymene)Cl 2 ] 2 with an alkaline halide, with dmoPTA (to obtain type I) and subsequent reaction with phosphines soluble in water or in organic solvents, according to a preferred embodiment. of the invention. Type II complexes are obtained by protonation of type I complexes with a strong or mild acid, such as HCI, HCF 3 SO 3 , H 2 S0 4 , H 3 P0 4 , HCI0 4 or CH 3 CH 2 COOH.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
El primer aspecto de la invención se refiere a complejos de rutenio solubles en agua, que comprenden derivados de dmoPTA (tipo I) y HdmoPTA (tipo II), con p-cimeno, haluros y fosfinas hidro y/o liposolubles:
The first aspect of the invention relates to water-soluble ruthenium complexes, comprising derivatives of dmoPTA (type I) and HdmoPTA (type II), with p-cymene, hydro and/or liposoluble halides and phosphines:
En las fórmulas anteriores I y II, Ru representa un átomo de rutenio; y Q, X representan, por igual o por separado: halógenos, fosfinas liposolubles o hidrosolubles; carga, n = 0, 1 , 2, 3. In the above formulas I and II, Ru represents a ruthenium atom; and Q, X represent, equally or separately: halogens, fat-soluble or water-soluble phosphines; load, n = 0, 1, 2, 3.
El átomo metálico de rutenio presenta una alta actividad biológica. Además, se ha observado que su actividad frente a biomoléculas se intensifica cuando se encuentra coordinado a la fosfina dmoPTA (complejos tipo I) y HdmoPTA (complejos tipo II). Se considera una realización preferida de la invención cualquier complejo de rutenio de fórmula I y II en el que Q e X representan el mismo o diferente ligando: F, Cl, Br, I; las fosfinas liposolubles trifenilfosfina, trimetilfosfinas, trietilfosfina, tripropilfosfina, tributilfosfina; las fosfinas hidrosolubles PTA (adamantanofosfina), dmPTA (dimetiladamantanofosfina), mPTA (metiladamantanofosfina) y fosfinas con grupos sulfonato, fosfato, carbonato, amina, amonio, carboxilato, alcohol, aldehidos y sus mezclas. En este contexto, mezclas se refiere a fosfinas que poseen dos o más grupos funcionales de los anteriormente citados. The ruthenium metal atom exhibits high biological activity. Furthermore, it has been observed that its activity against biomolecules is intensified when it is coordinated to the phosphine dmoPTA (type I complexes) and HdmoPTA (type II complexes). A preferred embodiment of the invention is considered to be any ruthenium complex of formula I and II in which Q and X represent the same or different ligand: F, Cl, Br, I; the fat-soluble phosphines triphenylphosphine, trimethylphosphines, triethylphosphine, tripropylphosphine, tributylphosphine; the water-soluble phosphines PTA (adamantanephosphine), dmPTA (dimethyladamantanephosphine), mPTA (methyladamantanephosphine) and phosphines with sulfonate, phosphate, carbonate, amine, ammonium, carboxylate, alcohol, aldehyde groups and mixtures thereof. In this context, mixtures refer to phosphines that possess two or more of the aforementioned functional groups.
El segundo aspecto de la invención hace referencia a los diferentes procedimientos para la obtención de los complejos de rutenio de fórmula general I y II. En los procedimientos descritos a continuación, los componentes y sustituyentes poseen el mismo significado que el dado anteriormente al describir los complejos de rutenio de formula general I y II. Los procedimientos parten bien del complejo de rutenio con p-cimeno, o bien de un halógeno de rutenio. En el primer caso, se produce la sustitución con el ligando dmPTA, que durante la reacción se abre dando lugar al compuesto HdmoPTA, o bien se parte directamente de la reacción con ese ligando, pero desprotonado. La combinación de las diferentes posibilidades de obtención dan lugar a cuatro procedimientos diferentes principales para obtener dichos complejos: a) Reacción del complejo [Ru(p-cimeno)Y2]2 (Y = halógeno) con dmPTA (CF3SC>3)2 (dmPTA = dimetiladamantanofosfina), y posterior reacción con
fosfinas solubles (Q) en agua o en disolventes orgánicos. Los complejos tipo I se obtendrían de los complejos tipo II por desprotonación con una base fuerte o de mediana fortaleza, tal como NaOH, KOH, NH3 (Figura 1 del presente documento). b) Reacción directa de un haluro de rutenio (RUY3; Y = F, Cl, Br, I) con p-cimeno, con dmPTA y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos. Los complejos tipo I se obtendrían de los complejos tipo II, por desprotonación con una base fuerte o mediana, tal como NaOH, KOH, NH3 (Figura 2 del presente documento). c) Reacción directa de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino (AlcY; Y = F, Cl, Br, I), con HdmoPTA(CF3S03) (para II) y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos. Los complejos tipo I se obtendrían del tipo II, por desprotonación con una base fuerte o mediana, tal como NaOH, KOH, NH3 (Figura 3 del presente documento). d) Reacción directa de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino, con dmoPTA (para obtener el tipo I) y posterior reacción con fosfinas solubles en agua o en disolventes orgánicos. Los complejos tipo II se obtienen por protonación de los complejos de tipo I con un ácido fuerte o mediano, tal como HCI, HCF3SO3, H2SO4, H3PO4, HCIO4 o CH3CH2COOH (Figura 4 del presente documento). The second aspect of the invention refers to the different processes for obtaining ruthenium complexes of general formula I and II. In the processes described below, the components and substituents have the same meaning as given above when describing the ruthenium complexes of general formula I and II. The procedures start either from the complex of ruthenium with p-cymene, or from a halogen of ruthenium. In the first case, substitution occurs with the dmPTA ligand, which opens during the reaction, giving rise to the HdmoPTA compound, or it starts directly from the reaction with that ligand, but deprotonated. The combination of the different possibilities of obtaining give rise to four different main procedures to obtain said complexes: a) Reaction of the complex [Ru(p-cymene)Y 2 ] 2 (Y = halogen) with dmPTA (CF 3 SC> 3 ) 2 (dmPTA = dimethyladamantanophosphine), and subsequent reaction with soluble phosphines (Q) in water or in organic solvents. Type I complexes would be obtained from type II complexes by deprotonation with a strong or medium strength base, such as NaOH, KOH, NH 3 (Figure 1 herein). b) Direct reaction of a ruthenium halide (RUY3; Y = F, Cl, Br, I) with p-cymene, with dmPTA and subsequent reaction with phosphines soluble in water or in organic solvents. Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base, such as NaOH, KOH, NH 3 (Figure 2 herein). c) Direct reaction of [Ru(p-cymene)Cl2]2 with an alkaline halide (AlcY; Y = F, Cl, Br, I), with HdmoPTA(CF 3 S0 3 ) (for II) and subsequent reaction with phosphines soluble in water or organic solvents. Type I complexes would be obtained from type II, by deprotonation with a strong or medium base, such as NaOH, KOH, NH3 (Figure 3 herein). d) Direct reaction of [Ru(p-cymene)Cl 2 ] 2 with an alkaline halide, with dmoPTA (to obtain type I) and subsequent reaction with phosphines soluble in water or in organic solvents. Type II complexes are obtained by protonation of type I complexes with a strong or mild acid, such as HCl, HCF 3 SO 3 , H 2 SO 4 , H 3 PO 4 , HCIO 4 or CH 3 CH 2 COOH (Figure 4 of this document).
A título ilustrativo de los procedimientos anteriores, en una realización preferente de la invención se realizarían los siguientes pasos:: i) Sustitución de un halógeno del complejo [Ru(p-cimeno)Y2]2 (Y = F, Cl, Br, I) con dmPTA(CF3SC>3)2 para dar lugar al complejo tipo II, [Ru(p- cimeno)HdmoPTA(Y2)]. El ligando dmPTA se transforma en el HdmoPTA al reaccionar con el disolvente (MeOH, EtOH, y alcoholes superiores hasta decanol tanto lineales como ramificados). Los complejos tipo I se obtendrían de los complejos tipo II, por desprotonación con una base fuerte o mediana tal como NaOH, KOH, NH3 u otras bases similares inorgánicas y orgánicas. ii) Reacción de los complejos obtenidos en la etapa anterior i), una vez purificados, con fosfinas hidro y/o liposolubles.
En una realización preferente alternativa de la invención, se realizarían los siguientes pasos: i) Reacción directa de una sal de rutenio (RUY3) (Y = F, Cl, Br, I), con p-cimeno y, posteriormente, con dmPTA(CF3SC>3)2 para dar lugar al complejo tipo II, [Ru(p-cimeno)HdmoPTA(Y2)]. Como el procedimiento anterior, el compuesto tipo I se obtiene por desprotonación del compuesto de tipo I. ii) Los complejos obtenidos en la etapa anterior, una vez purificados, se hacen reaccionar con fosfinas hidro y/o liposolubles. As an illustration of the above procedures, in a preferred embodiment of the invention the following steps would be carried out: i) Substitution of a halogen from the complex [Ru(p-cymene)Y 2 ] 2 (Y = F, Cl, Br, I) with dmPTA(CF3SC>3)2 to give rise to the type II complex, [Ru(p-cymene)HdmoPTA(Y 2 )]. The dmPTA ligand is converted to the HdmoPTA upon reaction with the solvent (MeOH, EtOH, and higher alcohols up to decanol both linear and branched). Type I complexes would be obtained from type II complexes, by deprotonation with a strong or medium base such as NaOH, KOH, NH3 or other similar inorganic and organic bases. ii) Reaction of the complexes obtained in the previous stage i), once purified, with hydro and/or liposoluble phosphines. In an alternative preferred embodiment of the invention, the following steps would be carried out: i) Direct reaction of a ruthenium salt (RUY3) (Y = F, Cl, Br, I), with p-cymene and, subsequently, with dmPTA( CF3SC>3)2 to give rise to the type II complex, [Ru(p-cymene)HdmoPTA(Y2)]. Like the previous procedure, the type I compound is obtained by deprotonation of the type I compound. ii) The complexes obtained in the previous stage, once purified, are reacted with hydro and/or liposoluble phosphines.
En una realización preferente alternativa de la invención, se realizarían los siguientes pasos: i) Los complejos tipo II se obtienen por reacción de [Ru(p-cimeno)CÍ2]2 con un halogenuro alcalino (AlcY; Y = F, Cl, Br, I) y posteriormente con HdmoPTA(CF3SC>3). A pH básico, se obtiene el complejo de tipo I. ii) Una vez purificados los complejos obtenidos en la etapa anterior, se hacen reaccionar con fosfinas hidro y/o liposolubles. In an alternative preferred embodiment of the invention, the following steps would be carried out: i) Type II complexes are obtained by reaction of [Ru(p-cymene)CÍ2]2 with an alkaline halide (AlcY; Y = F, Cl, Br , I) and later with HdmoPTA(CF3SC>3). At basic pH, the type I complex is obtained. ii) Once the complexes obtained in the previous stage have been purified, they are reacted with hydro and/or liposoluble phosphines.
En una realización preferente alternativa de la invención, se llevaría a cabo la reacción de [Ru(p-cimeno)CÍ2]2 con un halogenuro alcalino (AlcY; Y = F, Cl, Br, I) con el ligando dmoPTA. La posterior reacción con fosfinas solubles en agua o en disolventes orgánicos da lugar a los complejos finales tipo I. Los complejos tipo II se obtienen al acidificar los complejos tipo I con ácidos fuertes, tales como HCI, HCF3SO3, H2SO4, H3PO4, HCIO4, o intermedios como CH3CH2COOH. In an alternative preferred embodiment of the invention, the reaction of [Ru(p-cymene)CÍ2]2 with an alkali halide (AlcY; Y = F, Cl, Br, I) with the dmoPTA ligand would be carried out. The subsequent reaction with phosphines soluble in water or in organic solvents gives rise to the final type I complexes. Type II complexes are obtained by acidifying type I complexes with strong acids, such as HCI, HCF 3 SO 3 , H2SO4, H 3 PO4, HCIO4, or intermediates like CH 3 CH2COOH.
Todos estos procedimientos se llevan a cabo en un medio de reacción que comprende, preferentemente, un disolvente o mezcla de disolventes seleccionados entre agua, etanol, metanol, acetato de etilo, isopropanol, terbutanol, etilenglicol, diglima (Bis(2- metoxietil)éter), glima (Glicol dimetil éter), cloroformo, diclorometano, benceno, tolueno, acetona, tetrahidrofurano, dioxano, acetonitrilo. Es especialmente preferido el etanol, acetona y agua, y sus mezclas. All these procedures are carried out in a reaction medium that preferably comprises a solvent or mixture of solvents selected from water, ethanol, methanol, ethyl acetate, isopropanol, tertbutanol, ethylene glycol, diglyme (Bis(2-methoxyethyl) ether ), glyme (Glycol dimethyl ether), chloroform, dichloromethane, benzene, toluene, acetone, tetrahydrofuran, dioxane, acetonitrile. Ethanol, acetone and water, and mixtures thereof, are especially preferred.
Los procedimientos anteriores pueden llevarse a cabo en condiciones de temperatura de entre -60° C a 150° C y entre 0.5 y 100 atmósferas de presión, con o sin agitación. Preferiblemente, las reacciones se llevan a cabo a un rango de temperaturas de 5°C a 60°C y con presiones entre 0.5 y 10 atmósferas.
Las sales de rutenio (RL1Y3) usadas en el contexto de la presente invención se pueden seleccionar, preferentemente, de entre haluros de rutenio solubles. The above procedures can be carried out under temperature conditions between -60° C to 150° C and between 0.5 and 100 atmospheres of pressure, with or without stirring. Preferably, the reactions are carried out at a temperature range of 5°C to 60°C and with pressures between 0.5 and 10 atmospheres. The ruthenium salts (RL1Y3) used in the context of the present invention may preferably be selected from soluble ruthenium halides.
Otro aspecto de la invención se refiere a una composición con actividad biológica que comprende algún complejo de rutenio de formula general I y/o II, combinado con cualquier compuesto adicional con actividad biológica. Another aspect of the invention refers to a composition with biological activity that comprises a ruthenium complex of general formula I and/or II, combined with any additional compound with biological activity.
Los siguientes ejemplos específicos que se proporcionan aquí sirven para ilustrar la naturaleza de la presente invención. Estos ejemplos se incluyen solamente con fines ilustrativos y no han de ser interpretados como limitaciones a la invención que aquí se reivindica. The following specific examples provided herein serve to illustrate the nature of the present invention. These examples are included for illustrative purposes only and are not to be construed as limitations on the invention claimed herein.
Usando el primer procedimiento: Bajo una atmósfera de nitrógeno, en un matraz aforado se hace reaccionar [Ru(p-cimeno)CÍ2]2 (300 mg) con dmPTA(CF3SC>3)2 (dmPTA = bismetil- 1 ,3,5-triaza-7-fosfaadamantano) (376 mg) en 20 mL de EtOH. A las 4 horas, bajo fuerte agitación a temperatura ambiente, se añaden 200 mg de PTA (adamantanofosfina) y el conjunto se refluye durante 2 horas. La solución obtenida se filtra y por enfriamiento de las aguas de filtrado se obtiene el complejo [Ru(p-cimeno)CI(HdmoPTA)(PTA)](CF3SC>3)2 como un precipitado que se aísla por filtración, se lava con EtOH frío y se seca bajo vacío. Using the first procedure: Under a nitrogen atmosphere, [Ru(p-cymene)CÍ2]2 (300 mg) is reacted in a volumetric flask with dmPTA(CF3SC>3)2 (dmPTA = bismethyl- 1,3,5 -triaza-7-phosphaadamantane) (376 mg) in 20 mL of EtOH. After 4 hours, under strong stirring at room temperature, 200 mg of PTA (adamantanephosphine) are added and the whole is refluxed for 2 hours. The solution obtained is filtered and by cooling the filtrate waters, the complex [Ru(p-cymene)CI(HdmoPTA)(PTA)](CF3SC>3)2 is obtained as a precipitate that is isolated by filtration, washed with cold EtOH and dry under vacuum.
Usando el primer procedimiento: El complejo [Ru(p-cimeno)CI(HdmoPTA)(PTA)](CF3S03)2 (300 mg) se disuelve en una mezcla de 10 mL de EtOH/H20 (1:1). A temperatura ambiente, se añade KOH (30 mg). Por evaporación del disolvente bajo vacío a 5 mL el producto [Ru(p- cimeno)CI(dmoPTA)(PTA)](CF3S03)2 precipita, el cual se filtra, se lava con acetona, con éter etílico y se seca a vacío. Using the first procedure: The complex [Ru(p-cymene)CI(HdmoPTA)(PTA)](CF3S03)2 (300 mg) is dissolved in a mixture of 10 mL of EtOH/H 2 0 (1:1). At room temperature, KOH (30 mg) is added. By evaporation of the solvent under vacuum to 5 mL, the product [Ru(p-cymene)CI(dmoPTA)(PTA)](CF3S03)2 precipitates, which is filtered, washed with acetone, with ethyl ether and dried under vacuum. .
Usando el segundo procedimiento: En un balón de reacción se añade EtOH (30 mL) y, con fuerte agitación, RuCh (200 mg), p-cimeno (100 mg), y PTA (PTA = 1,3,5-triaza-7- fosfaadamantano) (100 mg). La mezcla de reacción refluye durante 4 horas, se enfría y evapora a 5 mL. El sólido formado se filtra, se lava con acetona, éter etílico y se seca a
vacío. El sólido se recristaliza en EtOH caliente, dando lugar a [Ru(p- cimeno)CI(HdmoPTA)(PTA)](CF3S03)2. Using the second procedure: EtOH (30 mL) is added to a reaction flask and, with strong stirring, RuCh (200 mg), p-cymene (100 mg), and PTA (PTA = 1,3,5-triaza- 7- phosphaadamantane) (100 mg). The reaction mixture is refluxed for 4 hours, cooled and evaporated to 5 mL. The solid formed is filtered, washed with acetone, ethyl ether and dried at empty. The solid is recrystallized from hot EtOH to give [Ru(p-cymene)CI(HdmoPTA)(PTA)](CF 3 S03)2.
Ejemplo 4 Example 4
Usando el tercer procedimiento: En un tubo de vidrio de 20 mm de diámetro se añade cloroformo (20 mL), [Ru(p-cimeno)Cl2]2 (400 mg), LiCI (40 mg) y HdmoPTA(CF3SC>3) (200 mg). A las 4 horas de reflujo se enfría y se añade NaTPPMS (NaPPh2PhSC>3) (600 mg). La suspensión se calienta a 50°C durante 3 horas, manteniendo la agitación y todo el sistema bajo atmósfera inerte. Al enfriar se forma un producto que se filtra y seca al aire. Dicho producto se disuelve en 10 mL de EtOH/agua (1:1) a 50°C. La disolución obtenida se enfría y se evapora bajo presión reducida obteniéndose el complejo [Ru(p- cimeno)CI(HdmoPTA)(TPPMS)](CF3S03). Using the third procedure: In a 20 mm diameter glass tube add chloroform (20 mL), [Ru(p-cymene)Cl2]2 (400 mg), LiCl (40 mg) and HdmoPTA(CF3SC>3) (200mg). After 4 hours of reflux, it is cooled and NaTPPMS (NaPPh2PhSC>3) (600 mg) is added. The suspension is heated at 50°C for 3 hours, maintaining stirring and the entire system under an inert atmosphere. On cooling a product is formed which is filtered and air dried. Said product is dissolved in 10 mL of EtOH/water (1:1) at 50°C. The solution obtained is cooled and evaporated under reduced pressure, obtaining the complex [Ru(p-cymene)CI(HdmoPTA)(TPPMS)](CF 3 S0 3 ).
Ejemplo 5 Example 5
Usando el cuarto procedimiento: En un balón de 100 mL con 80 mL de una mezcla CHCI3/EtOH (2:1) se añaden [Ru(p-cimeno)CI2]2 (1000 mg), KBr (140 mg) y dmoPTA (400 mg). Después de 4 horas a reflujo, se enfría y añaden Na3TPPTS (Na3P(PhSC>3)3) (2000 mg) y NaH (50 mg), calentándose la mezcla a reflujo. A las 4 horas, se enfría y la suspensión obtenida se filtra sobre una columna de 5 cm de altura y 3 cm de diámetro de zeolita, la cual se lava con dos porciones de 2 mL de agua. Por concentración de la disolución resultante se obtiene el complejo Na2[Ru(p-cimeno)Br(dmoPTA)(TPPTS)]. Using the fourth method: In a flask 100 mL with 80 mL of CHCI 3 / EtOH (2: 1) mixture was added [Ru (p-cymene) Cl 2] 2 (1000 mg), KBr (140 mg) and dmoPTA (400mg). After 4 hours at reflux, cool and add Na 3 TPPTS (Na3P(PhSC>3)3) (2000 mg) and NaH (50 mg), heating the mixture to reflux. After 4 hours, it is cooled and the suspension obtained is filtered over a zeolite column 5 cm high and 3 cm in diameter, which is washed with two 2 mL portions of water. By concentrating the resulting solution, the Na2[Ru(p-cymene)Br(dmoPTA)(TPPTS)] complex is obtained.
Ejemplo 6 Example 6
Usando el cuarto procedimiento: En un balón de 250 mL se añade con fuerte agitación EtOH (40 mL), [Ru(p-cimeno)CI2]2 (300 mg), Kl (70 mg), dmoPTA (100 mg) y PTA (110 mg). La suspensión se mantiene a reflujo durante 6 horas, manteniendo la agitación y bajo atmósfera inerte. La solución obtenida se enfría y se deja evaporar al aire, obteniéndose el complejo [Ru(p-cimeno)(l)(dmoPTA)(PTA)](l). Using the fourth procedure: In a 250 mL flask, EtOH (40 mL), [Ru(p-cymene)CI 2 ]2 (300 mg), Kl (70 mg), dmoPTA (100 mg) and PTA (110mg). The suspension is kept at reflux for 6 hours, maintaining stirring and under an inert atmosphere. The solution obtained is cooled and allowed to evaporate in the air, obtaining the complex [Ru(p-cymene)(l)(dmoPTA)(PTA)](l).
Los complejos con dos ligandos y tres ligandos HdmoPTA y dmoPTA, se obtendrían de una forma similar pero cambiando la estequiometría de los reactivos. The complexes with two ligands and three ligands HdmoPTA and dmoPTA, would be obtained in a similar way but changing the stoichiometry of the reagents.
Ejemplo 7
Según el primer procedimiento general de síntesis: bajo atmósfera inerte se hace reaccionar [Ru(p-cimeno)CÍ2]2 (300 mg) con dmPTA(CF3SC>3)2 (dmPTA = bismetil-1 ,3,5- triaza-7-fosfaadamantano) (752 mg) en 30 ml_ de EtOH. A las 6 horas se añaden 200 mg de PTA (adamantanofosfina) y el conjunto se refluye durante 4 horas. La solución obtenida se filtra y por enfriamiento de las aguas de filtrado se obtiene el complejo [Ru(p- cimeno)(HdmoPTA)2(PTA)](CF3SC>3)4 como un precipitado que se aísla por filtración, se lava con EtOH frío y se seca bajo vacío. Example 7 According to the first general synthesis procedure: under an inert atmosphere, [Ru(p-cymene)CÍ2]2 (300 mg) is reacted with dmPTA(CF3SC>3)2 (dmPTA = bismethyl-1,3,5-triaza-7 -phosphaadamantane) (752 mg) in 30 ml_ of EtOH. After 6 hours, 200 mg of PTA (adamantanephosphine) are added and the whole is refluxed for 4 hours. The solution obtained is filtered and by cooling the filtrate waters, the complex [Ru(p-cymene)(HdmoPTA)2(PTA)](CF3SC>3)4 is obtained as a precipitate that is isolated by filtration, washed with cold EtOH and dry under vacuum.
Usando el cuarto procedimiento general de síntesis: en un balón de 100 mL con 80 mL de una mezcla CHCh/EtOH (2:1) se añaden [Ru(p-cimeno)CÍ2]2 (1000 mg), KBr (140 mg) y dmoPTA (1200 mg). Después de 6 horas a reflujo se enfría la mezcla con agitación. La suspensión obtenida se filtra en una placa de vidrio sintetizado y el filtrado se lava con dos porciones de 10 mL de agua. Por concentración de la disolución resultante, se obtiene el complejo [Ru(p-cimeno)(dmoPTA)3]CÍ2. Using the fourth general synthesis procedure: in a 100 mL flask with 80 mL of a mixture CHCh/EtOH (2:1) [Ru(p-cymene)CÍ2]2 (1000 mg), KBr (140 mg) are added and dmoPTA (1200mg). After 6 hours at reflux, the mixture is cooled with stirring. The suspension obtained is filtered on a sintered glass plate and the filtrate is washed with two 10 mL portions of water. By concentration of the resulting solution, the complex [Ru(p-cymene)(dmoPTA)3]CÍ2 is obtained.
Los compuestos multimetálicos se obtendrían a partir de los complejos con uno, dos o tres HdmoPTA o dmoPTA, por reacción con sales metálicas. Multimetallic compounds would be obtained from complexes with one, two or three HdmoPTA or dmoPTA, by reaction with metal salts.
Una suspensión de [Ru(p-cimeno)(HdmoPTA)2(PTA)](CF3SC>3)4 (250 mg) se hace reaccionar con KOH (40 mg) y cuando el conjunto se disuelve completamente, se añade ZnCÍ2 (100 mg) en EtOH se refluye durante 6 horas. Por enfriamiento de la disolución resultante se obtienen en
forma de microcristales, los cuales se filtran bajo vacío, se lavan con dos porciones de 10 mL de EtOH, y se secan bajo vacío. A suspension of [Ru(p-cymene)(HdmoPTA)2(PTA)](CF3SC>3)4 (250 mg) is reacted with KOH (40 mg) and when the whole dissolves completely, ZnCÍ2 (100 mg) in EtOH is refluxed for 6 hours. By cooling the resulting solution, they are obtained in form microcrystals, which are filtered under vacuum, washed with two portions of 10 mL of EtOH, and dried under vacuum.
El complejo
(200 mg) suspendido en 50 mL de MeOH se hace reaccionar con CoBr2 (120 mg). El conjunto se refluye durante 6 horas y la disolución resultante se deja enfriar lentamente. El polvo blanco obtenido, el complejo [Ru(p-
se filtra bajo vacío, se lava con dos porciones de 10 mL de EtOH y 5 mL de Et20, y finalmente se seca bajo presión reducida.
Los complejos multimetálicos se obtienen por reacción de los anteriores por reacción entre ellos o con otros complejos metálicos. the complex (200 mg) suspended in 50 mL MeOH is reacted with CoBr2 (120 mg). The whole is refluxed for 6 hours and the resulting solution is allowed to cool slowly. The white powder obtained, the complex [Ru(p- it is filtered under vacuum, washed with two portions of 10 mL of EtOH and 5 mL of Et 2 0, and finally dried under reduced pressure. Multimetallic complexes are obtained by reaction of the above by reaction between them or with other metal complexes.
Ejemplo 11 Example 11
Una suspensión de
(150 mg) se hace reaccionar con AgCF3SO3 (30 mg) en 30 mL de MeOH. Después de 5 horas de agitación a temperatura ambiente se filtra el precipitado blanco-negro formado, y se lava con tres porciones de 5 mL de EtOH a 50 °C. El conjunto de las aguas de filtrado se concentran hasta 2 mL y se añade 5 mL de Et2O El precipitado formado se filtra, y se recristaliza en 20 mL de CHCI3/acetona. El producto [Ru(p-cimeno)(PTA){(dmoPTA-
precipita como un polvo microcristalino, que se filtra en una placa de vidrio poroso, se lava con dos porciones de 5 mL de EtOH a 5 °C, y se seca bajo vacío. A suspension of (150 mg) is reacted with AgCF3SO3 (30 mg) in 30 mL MeOH. After 5 hours of stirring at room temperature, the white-black precipitate formed is filtered and washed with three portions of 5 mL of EtOH at 50 °C. All the filtrate water is concentrated to 2 mL and 5 mL of Et2O is added. The precipitate formed is filtered and recrystallized from 20 mL of CHCl3/acetone. The product [Ru(p-cymene)(PTA){(dmoPTA- it precipitates as a microcrystalline powder, which is filtered on a fritted glass plate, washed with two 5 mL portions of EtOH at 5 °C, and dried under vacuum.
Ejemplo de propiedades anticancerígenas de este tipo de compuestos Example of anticancer properties of this type of compounds
Como ejemplo ilustrativo de las propiedades anticancerígenas de los compuestos de la invención, el complejo
mostró una actividad antiproliferativa indicada por el factor de vida media de supervivencia de las células (IC50) de 32.09±0.30 mM frente al del cisplatino que, en el mismo experimento, fue de 45.6±8.08 mM. Tres ejemplos de compuestos bi-heterometálicos que se obtendrían a partir de ese compuesto presentan una mejor actividad como muestra su IC50: IC50 Ru-Zn: 9.07±0.27;
As an illustrative example of the anticancer properties of the compounds of the invention, the complex showed an antiproliferative activity indicated by the cell survival half-life factor (IC50) of 32.09±0.30 mM against that of cisplatin which, in the same experiment, was 45.6±8.08 mM. Three examples of bi-heterometallic compounds that would be obtained from this compound show better activity as shown by their IC50: IC50 Ru-Zn: 9.07±0.27;
Claims
1.- Complejo de rutenio caracterizado por que comprende un derivado de Ru con p-cimeno y dmoPTA, según la fórmula (I):
donde: 1.- Ruthenium complex characterized in that it comprises a derivative of Ru with p-cymene and dmoPTA, according to formula (I): where:
Ru representa un átomo de rutenio; Ru represents a ruthenium atom;
Q y X, que son iguales o diferentes entre sí y representan un halógeno, o una fosfina liposoluble o hidrosoluble; n = 0, 1, 2, 3; representa la carga del complejo. Q and X, which are the same or different from each other and represent a halogen, or a fat-soluble or water-soluble phosphine; n = 0, 1, 2, 3; represents the charge of the complex.
2.- Complejo de rutenio según la reivindicación anterior, donde el dmoPTA está protonizado formando HdmoPTA, según la fórmula (II):
2. Ruthenium complex according to the preceding claim, where the dmoPTA is protonated forming HdmoPTA, according to formula (II):
3.- Complejo de rutenio según cualquiera de las reivindicaciones anteriores, donde Q y/o X representa: 3.- Ruthenium complex according to any of the preceding claims, where Q and/or X represents:
- una trifenil fosfina, tribenzilfosfina, trietilfosfina y tripropilfosfina; - a triphenyl phosphine, tribenzylphosphine, triethylphosphine and tripropylphosphine;
- F, Cl, Br o I; - F, Cl, Br or I;
- una fosfina soluble en agua, seleccionada entre fosfinas de grupos sulfonato, fosfato, carbonato, amina, amonio, carboxilato, alcohol, aldehido o sus mezclas, adamantano fosfina (PTA) o sus derivados;
siendo Q y X iguales o diferentes entre sí. - a water-soluble phosphine, selected from phosphines of sulfonate, phosphate, carbonate, amine, ammonium, carboxylate, alcohol, aldehyde groups or mixtures thereof, adamantane phosphine (PTA) or its derivatives; Q and X being equal to or different from each other.
4 - Procedimiento de obtención de un complejo de rutenio según la reivindicación4 - Process for obtaining a ruthenium complex according to claim
1, caracterizado por que comprende la realización de las siguientes etapas: i) reacción de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino AlcY, siendo Y = F, Cl, Br, I, con dmoPTA; ii) sustitución de uno o dos haluros coordinados al metal por una fosfina soluble en agua y/o en disolventes orgánicos. 1, characterized in that it comprises carrying out the following steps: i) reaction of [Ru(p-cymene)Cl2]2 with an alkaline halide AlcY, where Y = F, Cl, Br, I, with dmoPTA; ii) substitution of one or two halides coordinated to the metal by a phosphine soluble in water and/or in organic solvents.
5.- Procedimiento de obtención de un complejo de rutenio según la reivindicación5. Process for obtaining a ruthenium complex according to claim
2, caracterizado por que comprende la realización de las siguientes etapas: i) sustitución de un haluro en [Ru(p-cimeno)Y2]2(CF3SC>3), siendo Y = F, Cl, Br, I, por un ligando dmPTA que, una vez coordinado, se transforma en el ligando HdmoPTA; ii) sustitución de uno o dos haluros coordinados al metal por una fosfina soluble en agua y/o en disolventes orgánicos. 2, characterized in that it comprises carrying out the following steps: i) replacement of a halide in [Ru(p-cymene)Y2]2(CF3SC>3), where Y = F, Cl, Br, I, by a ligand dmPTA which, once coordinated, transforms into the ligand HdmoPTA; ii) substitution of one or two halides coordinated to the metal by a phosphine soluble in water and/or in organic solvents.
6.- Procedimiento de obtención de un complejo de rutenio según la reivindicación 2, caracterizado por que comprende la realización de las siguientes etapas: i) reacción directa de una sal de rutenio RuY3, siendo Y = F, Cl, Br, I, con p-cimeno y dmPTA que, una vez coordinado, se transforma en el ligando HdmoPTA; ii) sustitución de uno o dos haluros coordinados al metal por una fosfina soluble en agua y/o en disolventes orgánicos. 6. Process for obtaining a ruthenium complex according to claim 2, characterized in that it comprises carrying out the following steps: i) direct reaction of a ruthenium salt RuY3, where Y = F, Cl, Br, I, with p-cymene and dmPTA which, once coordinated, transforms into the ligand HdmoPTA; ii) substitution of one or two halides coordinated to the metal by a phosphine soluble in water and/or in organic solvents.
7.- Procedimiento de obtención de un complejo de rutenio según la reivindicación 2, caracterizado por que comprende la realización de las siguientes etapas: i) reacción de [Ru(p-cimeno)Cl2]2 con un halogenuro alcalino AlcY, siendo Y = F, Cl, Br, I, y HdmoPTA(CF3S03); ii) sustitución de uno o dos haluros coordinados al metal por una fosfina soluble en agua y/o en disolventes orgánicos. 7. Process for obtaining a ruthenium complex according to claim 2, characterized in that it comprises carrying out the following steps: i) reaction of [Ru(p-cymene)Cl2]2 with an alkaline halide AlcY, where Y = F, Cl, Br, I, and HdmoPTA(CF 3 S0 3 ); ii) substitution of one or two halides coordinated to the metal by a phosphine soluble in water and/or in organic solvents.
8.- Procedimiento para obtener un complejo de rutenio según la reivindicación 1 por desprotonación con una base de un complejo según la reivindicación 2. 8. Process for obtaining a ruthenium complex according to claim 1 by deprotonation with a base of a complex according to claim 2.
9.- Procedimiento para obtener un complejo de rutenio según la reivindicación 2 por protonación con un ácido de un complejo según la reivindicación 1.
9. Process for obtaining a ruthenium complex according to claim 2 by protonation with an acid of a complex according to claim 1.
10.- Procedimiento para obtener complejos Ru-multimetálicos a partir de los complejos obtenidos por las reivindicaciones anteriores, por reacción de dichos complejos con sales de metales de transición con haluros, sulfato, nitrato, nitrito, fosfato, tiocianato, y cianuro, acetilacetonato y aminas. 10. Process for obtaining Ru-multimetallic complexes from the complexes obtained by the preceding claims, by reacting said complexes with transition metal salts with halides, sulfate, nitrate, nitrite, phosphate, thiocyanate, and cyanide, acetylacetonate and amines.
11.- Procedimiento para obtener complejos polimetálicos a partir de los complejos obtenidos por las reivindicaciones anteriores, por reacción de dichos complejos con sales de plata y sales de metales de transición con haluros, sulfato, nitrato, nitrito, fosfato, tiocianato, y cianuro, acetilacetonato y aminas. 11.- Process for obtaining polymetallic complexes from the complexes obtained by the preceding claims, by reaction of said complexes with silver salts and transition metal salts with halides, sulfate, nitrate, nitrite, phosphate, thiocyanate, and cyanide, acetylacetonate and amines.
12.- Procedimiento según cualquiera de las reivindicaciones 4-11 que comprende el uso de uno o más disolventes que comprenden agua, etanol, metanol, acetato de etilo, isopropanol, terbutanol, etilenglicol, diglima (Bis(2-metoxietil) éter), glima (Glicol dimetil éter), cloroformo, diclorometano, benceno, tolueno, acetona, tetrahidrofurano, dioxano y/o acetonitrilo, y/o sus mezclas. 12. Process according to any of claims 4-11 comprising the use of one or more solvents comprising water, ethanol, methanol, ethyl acetate, isopropanol, tertbutanol, ethylene glycol, diglyme (Bis(2-methoxyethyl) ether), glyme (Glycol dimethyl ether), chloroform, dichloromethane, benzene, toluene, acetone, tetrahydrofuran, dioxane and/or acetonitrile, and/or mixtures thereof.
13.- Procedimiento según cualquiera de las reivindicaciones 4-12, donde al menos uno de sus pasos se lleva a cabo, parcial o totalmente, en un rango de temperaturas comprendido entre -60° C y 150° C con o sin agitación, y presión comprendida entre 0.5 y 10 atm. 13. Process according to any of claims 4-12, where at least one of its steps is carried out, partially or totally, in a temperature range between -60 ° C and 150 ° C with or without stirring, and pressure between 0.5 and 10 atm.
14.- Procedimiento según cualquiera de las reivindicaciones 4-13, que comprende el uso de sales de rutenio RuY3, siendo Y = F, Cl, Br, I, para la síntesis del complejo de rutenio y/o para la síntesis del complejo de p-cimeno. 14. Process according to any of claims 4-13, comprising the use of RuY3 ruthenium salts, where Y = F, Cl, Br, I, for the synthesis of the ruthenium complex and/or for the synthesis of the ruthenium complex p-cymene.
15.- Procedimiento según cualquiera de las reivindicaciones 4-14, que comprende el uso de sales de haluros alcalinos desde fluoruros hasta ioduros. 15. Process according to any of claims 4-14, comprising the use of alkali halide salts from fluorides to iodides.
16.- Complejo de rutenio según cualquiera de las reivindicaciones anteriores para su uso como un medicamento. 16. Ruthenium complex according to any of the preceding claims for use as a medicament.
17.- Complejo de rutenio según cualquiera de las reivindicaciones anteriores para su uso en el tratamiento del cáncer.
17.- Ruthenium complex according to any of the preceding claims for use in the treatment of cancer.
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| CN115227815A (en) * | 2022-05-05 | 2022-10-25 | 深圳市龙华区妇幼保健院(深圳市龙华区妇幼保健计划生育服务中心、深圳市龙华区健康教育所) | Nano composite material based on palladium-ruthenium hybrid nanoenzyme, and preparation method and application thereof |
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| ES2891137A1 (en) | 2022-01-26 |
| EP4180043A1 (en) | 2023-05-17 |
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